Cue Biopharma, Inc. Q3 FY2022 Earnings Call

Greetings, and welcome to the Cue Biopharma Update Call. A question-and-answer session will follow the presentation. As a reminder, this conference is being recorded. I would now like to turn the conference over to Dan Passeri, Cue Biopharma's Chief Executive Officer. Thank you, sir. Please begin.

Thank you, and good afternoon, everyone. Before I begin, I'd like to remind everyone that you have the slides in front of you that you need to operate manually, and we will notify you what slide we are on. Joining me on today's call is Dr. Anish Suri, our President and CFO; Dr. Ken Pienta, our Acting Chief Medical Officer; and Dr. Matteo Levisetti, our Senior Vice President of Clinical Development; as well as Kerri Millar, our Chief Financial Officer. This conference is being recorded and will be available on our website for the next 30 days. As a reminder, and as shown here on Slide number 2, this presentation and overview may contain some forward-looking statements, and any forward-looking statements made during this call represent the company's views only as of today, November 14, 2022. Our agenda for today's call is shown on the next slide, Slide 3. I'll begin by providing an overview of our competitive and strategic positioning based upon data from both our monotherapy trial of CUE-101 as well as the data just recently reported at SITC from our CUE-101 and KEYTRUDA combination trial. Anish will provide a review of this data in further detail momentarily. But first, I want to provide context pertaining to the underlying implications and importance of the data sets observed to date. As you are aware, the ultimate promise of immunotherapy is to enable the intrinsic potential of a patient's immune system to recognize and kill cancer. We believe through our representative data generated from both our monotherapy trial and combination trials of CUE-101, our IL-2-based Q100 series is now well positioned to become a first-in-class selective T cell engager and best-in-class IL-2 for cancer immunotherapy, as shown here on Slide number 4. The data bolsters our belief that the demonstrated mechanism of action and resulting activation and amplification of cancer-specific T cells will mechanistically complement and enhance therapeutic benefit derived from checkpoint inhibition, such as PD-L1 inhibitor KEYTRUDA. We believe the compilation of data from both the monotherapy and combination trials supports our central thesis of selective activation of cancer-specific T cells while avoiding systemic immune activation will enhance the desired antitumor efficacy. The recent data presented at SITC positions us well to push forward and potentially transform cancer therapy where patients in our own immune systems can be harnessed to the fullest extent to eradicate cancer. I'm now going to turn the call over to Anish who will provide a brief synopsis and overview of the key mechanistic features of our selective T-cell engager, the IL-2-based CUE-100 series, and I'll then turn the call over to Ken and Matteo to review the supporting efficacy data that has emerged from the monotherapy trial and provide an update from our recent SITC presentation pertaining to the current efficacy data from our combination of CUE-101 with KEYTRUDA in frontline HPV positive head and neck squamous cell carcinoma patients.

Thanks, Dan, and welcome to all listening to this update. As noted in the next slide, we all appreciate the fact that selective activation of tumor-specific T cells is central to successful outcomes for cancer immunotherapy. However, there are biological constants that nature has imposed that must be considered when thinking about tumor-specific T cells. One, the frequency of tumor-specific T cells in the patient is extremely low; greater than 99.9% of T cells in the patient have no relevance to cancer. So how does one go about selectively activating tumor-specific T cells while sparing the broad activation of all other T cells? Another biological constant is the fact that the only unique marker on an antitumor T cell is the tumor-specific T cell receptor or TCR. There are no other cell surface markers that exhibit an absolute fidelity to the anti-tumor T cell repertoire as the tumor-specific TCR. For example, PD-1 expression is a shared phenotypic marker or CD8 expression is a shared lineage marker, but neither are unique to an antitumor T cell. Hence, to exploit this unique selectivity, we've developed the Immuno-STAT platform to harness the TCR specificity to activate tumor-specific T cells. We believe, as supported by our clinical data, that this approach is differentiated in terms of both safety and efficacy outcomes over other modalities that attempt to activate the immune system in a nonselective manner. The next slide, Slide 6, depicts the core structure of an immuno-STAT molecule derived from our IL-2-based CUE-100 series, which is the major focus of today's presentation. As shown here, the CUE-100 series immuno-STAT harness the TCR selectivity via the stabilized peptide HLA molecule to target an affinity attenuated IL-2 variant selectively to tumor-specific T cells. The co-signaling via the TCR and IL-2 receptors on the anti-tumor T cell results in T cell activation and expansion. In contrast, if this molecule encounters the vast majority of irrelevant T cells in the patient, which is greater than 99.9% of irrelevant non-tumor-specific T cells, the attenuated IL-2 on its own is very weak. Hence, with this unique bias, we have created a therapeutic index for IL-2, allowing selective targeting on tumor-specific T cells over all other cells. Two additional aspects of the CUE-100 series are important to appreciate. While the primary core IL-2 framework is largely conserved between different therapeutic candidates, the primary difference from one therapeutic candidate to the next is a 9 to 10 amino acid T cell epitope depicted by the yellow circle in the diagram on the slide. Due to this conserved structure, we believe the clinical proof of concept with our first clinical candidate, CUE-101, has validated the entire platform. This conclusion is supported by the IND approval by the FDA earlier this year for our second clinical candidate, CUE-102, where, based on the clinical safety data from CUE-101, we did not need to perform any additional IND-enabling toxicology studies and were allowed to start the CUE-102 trial at a 1 mg/kg dose, which is a clinically active dose from our experience with CUE-101. Both CUE-101 and CUE-102 are 99% sequence identical except for the 9 to 10 amino-acid T cell epitope. CUE-101 targets a T cell epitope from human papillomavirus for HPV-driven cancers, such as head and neck cancer, while CUE-102 targets a T cell epitope from Wilms Tumor 1 or WT1, an oncofetal antigen widely expressed by many solid and hematological cancers. The other key aspect of the CUE-100 series Immuno-STATs pertains to their favorable stability and manufacturability metrics as a biologic platform. These are antibody Fc fusion proteins that follow established manufacturability and CMC protocols from many decades of commercial monoclonal antibody production. The shelf stability for the CUE-101 GMP drug product, our first clinical candidate, is greater than 36 months, which underscores the robustness of rational protein engineering. Let's move to the next slide, Slide 7. Based on the generation of a therapeutic index for IL-2 by selectively targeting tumor-specific T cells, we believe that the CUE-100 series has the potential to be the best-in-class IL-2 modality for cancer immunotherapy. As shown here, the improved safety and tolerability coupled with the antitumor T cell selectivity positions the CUE-100 series in a significantly different bracket when compared to other IL-2 variants that are being pursued. In fact, most of the focus of other IL-2 variants has been on modulating IL-2 receptor interactions with little thought towards antitumor T cell selectivity. This lack of biological relevance will continue to generate suboptimal clinical outcomes as recently evidenced with the clinical data sets from the recent trials from the PEGylated IL-2 and the non-alpha IL-2 modalities. Finally, let's move to Slide 8 that highlights supportive data for biological selectivity and activity of the IL-2-based CUE-100 series. The panel on the left shows selective engagement of the CUE-100 series immuno-STAT with an antigen-specific T cell. These data were generated by the lab of Dr. Michael Dustin at the University of Oxford. Dr. Dustin has been a pioneer in describing the T cell immune synapse that leads to downstream activation and effective function. As shown here, the CUE-100 series immuno-STAT only forms an immunological synapse shown in green with the antigen-specific T cells when both the TCR and IL-2 signals are operational. The same molecule with an irrelevant T cell, as shown in the bottom left panel, demonstrates no immune synapse in the absence of TCR engagement. The middle panel shows selective expansion of tumor-specific T cells from primary human blood samples, while no off-target effects are noted with irrelevant T cell specificity. This is exactly in line with the molecular design of the drug that selectively expands tumor-specific T cells while sparing all other non-specific T cells. The panel on the right shows intratumoral infiltration and expansion of tumor-specific T cells in an HPV-driven cancer model in mice. Note that in this study, not many T cells are evident in the vehicle-treated mice or in mice treated with the anti-PD-1 antibody alone. In contrast, a significant number of T cells are present after monotherapy with CUE-100 series Immuno-STAT and this population is further enhanced in combination with anti-PD-1 antibody treatment. We believe the ability of the CUE-100 series molecules to turn a cold tumor hot by selectively activating the right T cells is a key differentiating feature of our drug design. Similar observations are also evident from the early emerging data from the ongoing mechanistic clinical trial with CUE-101 in a neoadjuvant setting in locally advanced head and neck cancer patients. With that background on our differentiated mechanism for IL-2 targeting, I'd like to now pass the call to Ken Pienta and Matteo Levisetti to share the exciting clinical data from the ongoing trials with head and neck cancer patients with our lead clinical candidate, CUE-101.

Thanks, Anish. As shown on the next slide, data from the ongoing clinical trials with CUE-101 as monotherapy and in combination with pembrolizumab have provided clinical proof-of-concept or POC and derisking of the Immuno-STAT platform. We're pleased to be presenting our updated data from the ongoing CUE-101 Phase I trial, as both a single-agent monotherapy and in third line and beyond patients, as well as the encouraging emerging data from the combination study with pembrolizumab in first-line patients. As previously and consistently stated by us, we believe CUE-101's mechanism of action, as evidenced by the ongoing data generated to date, provides effective and tolerated dose levels enabling selective stimulation of tumor-specific T cells — recurrent head and neck cancer is a tough and curable disease. The data we have observed throughout the monotherapy trial enhances our confidence that CUE-101 is stimulating cancer-specific T cells in a subset of these patients with resulting antitumor effect. Furthermore, and more importantly, we continue to observe an evolving trend of enhanced survival. Key observations in patients treated with CUE-101 monotherapy in third line and beyond include, as detailed on Slide 10, a demonstration of a single-agent antitumor efficacy, evidenced by RECIST-based PR and durable stable disease in third line and recurrent metastatic head and neck squamous cell carcinoma and a median overall survival benefit emerging from the survival follow-up in the RP2D cohort. The robust data on CUE-101's activity in monotherapy and in combination with pembrolizumab has triggered the granting of Fast Track designation status for the treatment of patients in both first and third line settings. As shown on Slide 11, CUE-101 demonstrates well-behaved pharmacokinetics with low interpatient variability at the recommended Phase II dose of 4 mg per kg. Exposure is maintained throughout multiple cycles of treatment without any attenuation of PK parameters consistent with the lack of clinically relevant immunogenicity. CUE-101 treatment results in sustained increase in NK cells, a positive attribute of an antitumor response as the NK cells may assist in tumor killing. And as you can see in the lower left panel with only a modest and transient increase in Tregs. As shown in the middle panel, we have observed robust expansion of tumor-specific E7 reactive T cells in the peripheral blood of patients as early as 1 week after administration of CUE-101. In the right panel, paired and post-treatment biopsies demonstrate an increase in tumor-infiltrating T cells and tumor necrosis. In addition to the favorable PK and PD just described, patients with advanced HPV-positive head and neck squamous cell cancer are experiencing patterns of clinical benefit. The examples are shown in the next slide, Slide 12. Patient A experienced a durable partial response with an approximately 60% reduction in tumor burden that was evident starting at 6 weeks after 2 cycles of CUE-101 and lasted close to 1 year. Patient B, who remains on treatment at the present time, has had stable disease with tumor burden reduction of approximately 20% observed at week 48 and notably complete disappearance of HPV cell-free circulating tumor DNA in the blood observed at week 6 and maintained. The undetectable HPV DNA is an increasingly recognized biomarker of disease activity and suggests the possibility of a pathologic complete response and cure in this patient who will likely have a surgical resection of their solitary cancer lesion early next year. Patient C has experienced tumor reduction after a prolonged period on the drug, where no RECIST-based objective response was initially observed. This patient treated with CUE-101 at 2 mg/kg, appeared to demonstrate tumor growth even beyond the 20% threshold used by RECIST criteria. However, based upon the overall clinical status, the patient continued on treatment. After approximately 6 months, the tumor began to shrink, and the patient remains on therapy 14 months after starting treatment with CUE-101. This observation is consistent with observations made by others that demonstrate that the kinetics of T cell antitumor activity may manifest over a long period of time. The next slide, Slide 13, conveys our ongoing survival swimmer plot for the 20 patients dosed at the RP2D of 4 mg per kg. The emerging Kaplan-Meier estimate of a median overall survival of greater than 13 months compares favorably to the survival of approximately 8 months observed in patients treated in the second line in the KEYNOTE-040 trial of pembrolizumab. As any experienced oncologist understands, the survival in third line treatment is expected to be less as the disease further develops and becomes more unstable. Our continued evolving data supports the premise that treatment with CUE-101 is clearly trending to increase survival in the third-line setting for patients with head and neck cancer. This data has encouraged our principal investigators and they are certainly aligned with our position that this provides us with a promising path forward to a registrational trial. The demonstration of monotherapy activity bolsters our belief that we should see complementary mechanistic effects in combination with pembrolizumab. As a reminder, the data from the monotherapy clearly supports that CUE-101 increases the number of antigen-specific T cells. It is likely that these T cells will have greater freedom to kill with concurrent inhibition of the PD-1 pathway, a major mechanism used by cancer cells to prevent immune-mediated killing. I will now pass the call to Matteo to provide an overview of the exciting emerging data and clinical efficacy of CUE-101 in combination with pembrolizumab.

Thanks, Ken. As shown on Slide 14, even at our starting dose of 1 mg per kg, we observed a patient with durable stable disease. At 2 mg per kilogram, we observed a patient with durable stable disease and a patient with a deep partial response who continues on therapy today. At the presumed recommended Phase II combination dose, we have not only not observed any dose-limiting toxicities, but we have observed a 40% objective response rate with 4 now confirmed partial responses and another 4 patients with stable disease that are currently being monitored on the trial. This compares favorably with the reported overall response rate of single-agent pembrolizumab of 19% in the first-line treatment setting, as observed in the KEYNOTE 48 trial. Let me show you 2 examples of these partial responses. Slide 15 shows the patient from Cohort 2, demonstrating a decrease in all 4 of their target lesions, including 2 liver lesions as seen on the 2 scans on the left. I want to emphasize that this is not just shrinkage in lymph nodes, but shrinkage of visceral metastatic tumor disease in the liver. On the upper right side, the graph depicts the absolute measurements of the 4 target lesions with the best overall response of approximately 70%. To any oncologist, this is a significant and meaningful response. This patient has also demonstrated a clearing of the circulating cell-free HPV DNA, which is ongoing. As mentioned before, circulating cell-free HPV DNA continues to be developed and used by our principal investigators as a potential surrogate for response. As shown in Slide 16, one of the patients with a confirmed partial response from Cohort 3 also demonstrated reductions in all 4 target lesions, including 2 lung lesions as well as clearing of their circulating cell-free HPV DNA. As you can see on the scans on the left, target lesions 3 and 4, both are very substantial metastatic disease lesions in the lung, decreased in size by greater than 60%. The absolute measurements of the 4 target lesions are depicted in the right upper panel. And as we have seen in the last patient, this patient completely cleared their tumor DNA from the blood at a time concurrent with the observed RECIST response. In the next slide, Slide 17, we see that all of the patients treated in the combination trial are still alive, 5 of whom have already passed the median overall survival observed in the KEYNOTE-48 trial, which was 12.3 months. We also anticipate an increase in progression-free survival as the data from the 4 mg per kg plus pembrolizumab cohort matures. Taken together, the observed doubling of overall response rate, 40% compared to the historical 19% observed in KEYNOTE-48 with pembrolizumab monotherapy, along with an increase in median PFS will expand patient reach and may provide an attractive therapeutic option for patients with recurrent metastatic head and neck squamous cell carcinoma in the first line setting. A high-level perspective of study designs to support approval of both monotherapy and combination with pembrolizumab is presented on Slide 18. We are excited by the preliminary data in the ongoing monotherapy and combination trial and plan to get clarity on the registrational path to approval for both lines of therapy. The recent granting of Fast Track designation further underscores our confidence in realizing successful regulatory interactions. I'm also happy to report that we have treated our first patient with CUE-102, which targets Wilms tumor 1-positive tumors in the trial that is enrolling patients with advanced colorectal, gastric, pancreatic, and ovarian cancers. As shown on Slide 19, CUE-102 and CUE-101 share 99% amino acid sequence identity. This enabled us to significantly decrease the development time and cost of CUE-102 as we were not required by the FDA to repeat IND-enabling toxicology studies for CUE-102, and we are also able to initiate the Phase I dose escalation study at 1 mg per kg, the dose at which we observed clear signs of biologic activity with CUE-101. As Slide 20 shows, we are performing the CUE-102 dose escalation study in colon, gastric, pancreatic, and ovarian cancers. This design offers us the ability to do monotherapy expansion studies in any or all of the indications being evaluated in the dose escalation phase of the trial. The trial is actively accruing and will be open at 15 sites around the United States. We plan to present additional data at an upcoming medical meeting. I will now turn the call over to Anish to talk more about our pipeline.

Thanks, Matteo. Moving on to the next slide, as you heard from the clinical update, we believe the clinical derisking by CUE-101 has essentially derisked our entire platform. As noted by Matteo, the recent IND acceptance for CUE-102, targeting WT1, underscores the strategic advantages of platform derisking accomplished by CUE-101, which also highlights the resource time and operational efficiencies. Furthermore, we believe the modularity of our platform, coupled with the clinical validation, positions us to generate a rich repository of therapeutic molecules targeting many cancers. Some examples of additional tumor antigens that can be effectively targeted such as mutated KRAS or MAGE-A4 are shown here. Furthermore, to extend the application of our platform to incorporate multiple T cell epitopes or even personalized neoantigens, we have created the NeoStat framework with an empty HLA molecule to which we can chemically conjugate any given tumor epitope. Here again, the core IL-2 variant and valency is conserved. The NeoStat platform expansion realizes significant time and cost efficiencies by having an off-the-shelf approach to selectively target multiple tumor antigens across many cancers. As one evaluates the potential of IL-2 for cancer immunotherapy, we believe our platform has cracked the code for selective targeting of this important cytokine to the tumor-specific T cell repertoire.

Thanks, Anish. Turning on to Slide 22, I'd like to provide a brief update on our financial results for the 3 months ended September 30, 2022. The company reported collaboration revenue of approximately $68,000 and $2.4 million for the 3 months ended September 30, 2022 and 2021, respectively. Research and development expenses were $7.6 million and $11.3 million for the 3 months ended September 30, 2022 and 2021, respectively. The decrease was primarily due to decreases in laboratory and drug substance manufacturing costs, employee compensation, licensing fees, and rent. General and administrative expenses were $3.5 million and $4.1 million for the 3 months ended September 30, 2022 and 2021, respectively. This decrease was primarily due to a decrease in stock-based compensation, rent, and professional and consulting fees incurred during the third quarter of 2022 compared to the same period in 2021. We ended the quarter with approximately $59.1 million in cash, cash equivalents, and marketable securities and working capital of approximately $51.5 million. Earlier today, we announced that we had entered into a securities purchase agreement with certain accredited investors for $30 million private investment in public equity or a PIPE financing. We believe our cash and cash equivalents and marketable securities as of September 30, 2022, along with the $30 million that we will receive from the PIPE financing will allow us to support the development of our Immuno-STAT platform, including the clinical development of CUE-101 and CUE-102 into 2024.

Yes. Thanks, Kerri. With the recent financing, extending runway upon closing, combined with the supportive and promising data from our ongoing clinical trial, we're now able to focus on core strategic initiatives to further enhance our competitive positioning to optimize shareholder value. The clinical data recently reported at SITC enhances our confidence in the breakthrough potential of our platform and the transformative nature of our approach to selectively modulate disease-relevant T cells directly in the patient's body. We believe we're now very well positioned to take the company to the next level and emerge as a leading provider of effective and well-tolerated T cell engagers with the potential of transforming cancer therapy. In the near term, we're focused on several core corporate development catalysts and strategic initiatives to further enhance our competitive positioning. Primarily among these core initiatives, the following milestones to enhance shareholder value, as shown on the next slide. With CUE-101 monotherapy expansion cohort and third line and beyond refractory and metastatic HPV positive head and neck cancer patients will have mature median overall survival data by the end of this year with a potential registration trial being defined by mid-next year. With CUE-101 plus pembrolizumab combination expansion cohort, we anticipate reporting on preliminary overall response rate in the second quarter of next year. On the full 20 patients with a potential registration trial being defined in the second half of the year. We are highly encouraged by the data reported at SITC on the first 10 patients and look forward to reporting on the full 20 of the 4 mg per kg cohort. Again, to remind you, we believe the data reported to date supports the premise that CUE-101, as representative of the Immuno-STAT platform CUE-100 series, demonstrates the potential of expanding patient reach and therapeutic benefit of checkpoint inhibition, placing us in a strategic position for corporate partnering. The CUE-102 monotherapy dose escalation trial is ongoing, targeting Wilms Tumor 1 expressing cancers. The evidence of clinical activity should be a catalyst for further validation and value enhancement of our platform. Data from this dose escalation should be reported by mid-2023, with significant potential market opportunities in WT1-positive cancer indications. We believe the differentiated therapeutic potential of the IL-2-based CUE-100 series, as evidenced by our current data sets, will further catalyze significant business development and corporate development opportunities for pipeline expansion addressing hematologic and solid cancers. We look forward to providing ongoing updates in the coming months and want to thank our shareholders for their support and shared vision and the potential of Cue Biopharma to transform the treatment of cancer, and we want to extend our gratitude to our employees, the Board of Directors, and most importantly, we want to thank the patients and their families for participating in our trials. Thank you all very much for your attention and interest, and I'd like to now turn the call back over to the operator for questions.

Thank you, sir. The first question we have is from Reni Benjamin from JMP Securities.

Congratulations on the data update at SITC. Maybe just to start off, can we talk a little bit, especially in the combination study, what are the typical treatments that you're seeing post-progression? And are you seeing in these first 10 patients any sort of recycling of checkpoint inhibitors and potentially getting a subsequent response in patients who maybe didn't have that before.

So Ren, this is Ken. Thanks for the question. So the reality is we don't know what's going on with those folks. This data we're collecting, but we really can't give you an update on what other therapies they might be getting afterward. It's across multiple sites, and there's no specific regimen that these folks are going to.

Got it. And then either for the monotherapy or the combination study. I don't think I saw this number, but I'll just ask it anyway. Do you have a median duration of response for either of those two?

No. We don't have that calculated because we won't calculate that until we get the final survival data in the monotherapy, and it's just too early to do that in the combo.

Got it. Switching topics to the neoadjuvant study, could you share how many patients have been enrolled? Have you been able to collect biopsy samples? Do you have any initial insights or takeaways to provide?

Yes. So the neoadjuvant study is really a spectacular opportunity for us to examine in the tissue itself, the effects of CUE-101 therapy. So we're obtaining in the neoadjuvant setting pre- and post-treatment biopsies. We've treated close to 10 patients to date. The preliminary data that we have in these paired biopsies demonstrates some of the findings that we've observed in patients; i.e., we have observed increases in NK cells pre- and post-treatment. We also observed findings consistent with the increase in tumor infiltrating lymphocytes that we've observed in the paired biopsies obtained in the patients in the CUE-101 trial.

I’ll jump back in the queue.

The next question we have is from Stephen Willey from Stifel.

Yes. Maybe just to follow up on Ren's question. I know you don't have a median duration of response for the combo just yet, but do you have the duration of response from the best responding combo patient, who I believe is no longer undergoing therapy?

If I can mention here, the duration of response in monotherapy is 42 weeks. So the confirmed PR that we observed in monotherapy at 4 mg per kg is really a very durable response. I think if we look at the swimmer plot — so Slide 17 from the — I'm sorry, swimmer from Slide 17 in the combination therapy, what clearly is evolving is an increase in progression-free survival. And so if you look at the length of time that patients remain on therapy and if you had to eyeball the median PFS, it really appears to be somewhere between 6 months and 7 months. In contrast to the PFS that was observed in KEYNOTE-48 of 3 months, it really appears that there's a differentiated signal with regard to progression-free survival. And one can infer, to come back to your question regarding the median time on treatment. I think PFS is a very good surrogate for that because our patients tend to stay on treatment without progression because the combination of CUE-101 and pembrolizumab is being so well tolerated.

Okay. And then what can you say about where you are on the development side with NeoStat? And to the extent that you've derisked the Q100 Series, how do you think about advancing NeoStat versus maybe just swapping in a different allelic variant of the Q100 series and trying to leverage some of the progress and the derisking that you've made to date on the platform?

Yes. Steve, this is Anish. Very, very good question. So there's two ways how we are thinking about this, Steve. Obviously, for antigens where we have very strong confidence in other alleles coming in that select for the tumor epitopes. KRAS is a very good example of that where HLA-A11 803, for example, there's very good data that's emerged, including some of the TCRT-based approaches that are being pursued for the mutated G12V G12D variant. So in that case, it makes very good sense, and that's what we've done, but it makes sense to go forward with a different allelic variant that gives us confidence of targeting that particular epitope from a primary tumor driver. The NeoStat framework, on the other hand, has been created on HLA-A2, which essentially just gives us excellent continuity for the pipeline because of the derisking and the nature of the impression we already have from 102. For example, this is another angle. That's how we look at it, except that the time to generation of the active drug product is going to be substantially lesser than making a separate antibody molecule as we have to do when the peptide is linked in like 101, 102, 103, etc. Both prongs are being pursued. In the NeoStat, we've had some data where we've had early proof-of-concept experiments and validation. We're now in the midst of optimizing our processes for conjugation and scale up, hoping with the intention of moving this towards a clinical application in the future.

Sure. Thank you.

The next question we have is from Mark Breidenbach from Oppenheimer.

Congrats on the update. Maybe a couple of quick ones for me. First, maybe a clarification question for Dan. Just with the language of defining potential registrational trials in 2023, both for the monotherapy and for combo. By defining the trial, do you mean finalizing the protocol or initiating the trial? What maybe you can just be a little more specific there. And then another question maybe on the science side; I'm just wondering if you're continuing to see evidence of clonal T cell expansion in the peripheral blood in the ongoing combination study. We saw some of that in the monotherapy part of the study. But it's been a while since I've seen some of those data presented. Is that being superseded by the circulating tumor HPV DNA? Or can we look forward to more of that sort of analysis once you have the full 20-patient cohort?

Sure. Thanks, Mark. I'll give you a broad overview of response to the first question, and then I'm going to turn it over to Matteo and maybe he and Anish can take the second question. So regarding the registration path, the reason we're putting it out as defining is we want to assess whether we want to approach both third line and frontline or determine whether we're just going to get a registration path to find, meet with the FDA to show confidence in the underlying support of data set and then continue on with the frontline because what we have to assess is how rapidly a registration path in the frontline could cannibalize the market in the third line sets; that is one of the factors we're looking at. But the key is for us to define based on the strength of the data and meet with the FDA to define the protocol, but I'll turn it over to Matteo.

Yes. No, thanks, Dan. So Mark, it's really an important question. What we really have is a harmonized regulatory strategy where we mutually leverage the data that's being acquired in monotherapy and in the data that's being acquired in combination. We have a planned interaction with FDA in the first quarter of next year. We will really use that as an opportunity to get as much clarity as possible with regards to registrational paths for both approval of monotherapy in the third line and beyond, as well as approval of combination therapy in the first line. In our experience, given the strength of our emerging combination data, the FDA will be very keen to partner with us to explore ways that would bring the combination therapy to patients as fast as possible. If the objective response rate of 40% continues to be observed in the additional 20 patients, we will then have a very compelling data set to discuss with FDA about the opportunity of pursuing an accelerated approval based on an overall response rate, which we're currently seeing is twice that of pembrolizumab monotherapy in the first line treatment setting.

Yes. And just to add on, Mark, to the question around PD for T cell analysis, that is very much planned for the combo. We just haven't executed on that and initiated. I would like to do a batch analysis with all these samples together as these patients are being recruited, just like we sort of started to do some of that for monotherapy. But I anticipate similar outcomes, if not even possibly higher frequencies based on some of our preclinical observations. So we'll share that when we generate the data.

All right. Luck on the progress.

Thank you, Mark.

Thank you. The next question we have is from Brian Soni from Bot.

This is Charlie on for Brian. So I just had a couple of quick ones. I was curious how we should think about comparing data between the CUE-101 and some of the other therapies that are in the HS NCC space, given that it's targeting HPV 16 positive patients. Like is that — do you think that's something that might come up with regulators given the literature tends to see it as having a better prognosis than HPV negative? And then secondly, if you could just give some color on how you're thinking about advancing 101 as a monotherapy? And what kind of hurdle do you think you're going to have to hit in terms of overall response rate, that would be great.

I'm happy to start there. With regards to the prognosis of patients with HPV-positive cancer, in contrast to those that are HPV negative, I think you point out a very relevant observation. It's true that they appear to do a little bit better at each line of therapy, but not that much better. So we have a host of really experts in HPV-driven head and neck cancer as investigators. The treatment effect and the benefit that's emerging in monotherapy is differentiated — factoring in what you're saying, which is accurate that HPV-positive patients may do a little bit better at each line of therapy. With regards to the registration path for monotherapy in the third line and beyond, we really have consensus among experts that if we demonstrate a median overall survival of 12 months in the monotherapy cohort, and currently, the median OS Kaplan-Meier estimate is at 13.3 months; that would really represent a very significant clinical benefit compared to the anticipated survivorship. So in the second-line setting, HPV-positive patients have a median OS of about 8 months. Thus, we're observing a treatment effect that goes now beyond 13 months, which translates to over a 50% improvement. We envision doing a very efficient trial of CUE-101 monotherapy versus investigator's choice of chemotherapy, powered based on the numbers mentioned.

Fantastic. That's very helpful. Thank you very much.

Thank you.

Our final question comes from Ted Tenthoff from Piper Sandler.

Two questions on 102 have been answered and excited about the progress you're making there. When it comes to 102, can you kind of share with us what you envision as the bore opportunity now that you've derisked the ImmunoStat platform with 101 in HPV-positive head and neck? Where could you go with 102?

Yes. Thanks, Ted. The importance of 102, as Anish stated, lies in the fact that it is an analog of 101. It's been derisked from the standpoint that we're able to start at 1 mg per kg with preclinical data on human blood samples even. We were able to show significant amplification of targeted T cells. So we're actually going into this with a lot of confidence. The importance of Wilms Tumor 1 is that it's overexpressed in a significant number of solid and hematologic cancers, including colorectal, pancreatic, ovarian, and glioblastoma, for instance. Any activity we see in this dose escalation phase is going to be a real catalyst in terms of demonstrating the modularity and reaffirming and validating this analog nature. It's the same framework; all we're doing is swapping out the epitope. So, it really will reinforce that concept of being able to swap out an epitope and have the molecule active against a different subset of T cells to address various cancers. I'm going to now hand it over to Matteo just to elaborate.

Yes. So really, a very good question. Clearly, you recognize that WT1 is overexpressed in many cancers. We decided to initiate development in a small basket of solid tumors, focusing on GI tumors, including colon, pancreatic, and gastric, as well as ovarian, to efficiently achieve several objectives, including demonstrating safety, tolerability, PK/PD in a defined population in a trial. However, we did design the protocol to allow for easy expansion into any of the 4 indications as we see early signals of activity. Additionally, glioblastoma is another promising indication. As soon as there is some data in a small number of patients, it would be very easy to amend the protocol and include cohorts of patients, including glioblastoma; for liquid tumors, it is highly derisked with TCRT experience with WT1 as a target. AML and myelodysplastic syndrome are among the liquid tumors we are considering as we broaden the potential applications for WT1.

This concludes our question-and-answer session. I would now like to turn the conference back over to Dan Passeri for closing remarks. Please go ahead, sir.

Okay. Again, we want to thank everyone for your time and interest in our ongoing progress, and we look forward to providing you with updates in the coming months. Thank you again and take care, everyone.

Thank you, sir. Ladies and gentlemen, that then concludes today's conference. Thank you for joining us. You may now disconnect your lines.